DESCRIPTION: The research program outlined herein is directed toward the design and development of novel general strategies for the syntheses of natural and unnatural products that possess significant biological activity. During the course of these investigations, the scope and limitations of selected reactions and processes are to be explored in the context of the total synthesis of complex molecules, and new methods for carbon-carbon bond formation and functional group manipulation are to be discovered. It is noted that the specific synthetic objectives include completion of the total syntheses of several biologically important natural products including the antifungal antibiotic ambruticin and the macrolide antibiotic erythromycin B. The basic strategies for the syntheses of each of these compounds are convergent and involve the stereoselective elaboration of furans and hydropyrans derived therefrom. New methods and catalysts for the asymmetric synthesis of 1,2,3-trisubstituted cyclopropanes and for the stereoselective construction of trisubstituted olefins are to be developed and applied. It is reported that the approach to erythromycin B is unique and involves the macrolactonization of a glycosylated seco-acid derivative. The principal investigator indicates that simple analogues of the erythromycins that bear the critical carbohydrate residues on a simplified molecular framework will be designed and prepared in an effort to elucidate the erythromycin pharmacophore and ultimately to identify novel, orally-active antibiotics. He further notes that several new biologically active targets have been selected that will serve as the forum for the invention of new chemistry and indicates that example that the total synthesis of FR900482, a potent anticancer candidate related to the clinically active mitomycins will be undertaken. He states that the key element of his strategy for the synthesis of this intriguing alkaloid entails an olefin metathesis reaction to construct a highly functionalized nitrogen heterocycle. It is reported that a concise approach to zaragozic acid A, a novel squalene synthase inhibitor, has been devised that features a vinylogous aldol reaction to assemble the carbons constituting the bicyclic core structure. It is noted that quantities of the natural products and selected congeners will be prepared for submission to C.P. Starks, Inc., Eli Lilly Company, Merck, Abbott Laboratories, and Glaxo for biological evaluation as potential antibiotics and as antifungal, hypocholesterolemic and anticancer agents.